Systemic lupus erythematosus or lupus is a polygenic autoimmune disease characterized by high levels of anti-nuclear autoantibodies, and several cellular abnormalities involving B-cells. myeloid cells and other lineages. The genetic basis of lupus remains to be solved. Although the approximate positions of several disease susceptibility loci in murine lupus have been elucidated in many different models, the identity of the culprit genes within the identified loci remain elusive. In particular, this is true of the BXSB strain that develops lupus spontaneously. We have recently identified 2 potential candidate genes that appear attractive as culprit genes for lupus in this model, based on expression differences, intriguing sequence polymorphisms and demonstrated functional differences. The goal of this proposal is to test the candidacy of these 2 molecules as potential culprit genes for BXSB lupus, and to ascertain how these genes might influence the function of B-cells and myeloid cells, using in vitro and in vivo approaches. In addition, we will assess the origins and pathogenic contributions of heightened SDF1/CXCR4 activity in lupus. Given that very little is currently known about the genetics of lupus, or about why B-cells and myeloid cells are hyperactive in lupus, the proposed studies could greatly boost our understanding of this disease. Gaining a clear understanding of the genetic and molecular basis of lupus is essential before more targeted therapeutic strategies can be devised for this disease.